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Oxytocin receptor linked signaling pathways resulting in myometrial contraction. Binding of OT to OTR activates Gαq/11 and then PLC, which hydrolyses PIP2 to InsP3 and DAG. InsP3 causes release of Ca2+ from the sarcoplasmic reticulum, while DAG activates PKC. Gαq/11 also causes activation of voltage-regulated Ca2+ channels and Ca2+ entry into the cells. Ca2+ binds to calmodulin, and the Ca2+-calmodulin complex activates MLC kinase, resulting in myometrial contraction. Both OTR and PKC activate the MAPK cascade, while OTR and MAPK result in increased cPLA2 activity. Increased cPLA2 activity and MAPK activation result in prostaglandin production, which also contributes to the contractile effect. The activation of the RhoA-ROK cascade by the OTR is another pathway that results in increased MLC phosphorylation and myometrial contraction. OT: oxytocin, OTR: oxytocin receptor, PLC: phospholipase, PIP2: phosphatidylinositol 4,5-bisphosphate, InsP3: inositol 1,4,5- triphosphate, DAG: diacylglycerol, PKC: protein kinases type C, MLC: myosin light-chain, MAPK: mitogen-activated protein kinase, cPLA2: cytosolic phospholipase A2, ROK: RhoA associated protein kinase.
Source publication
Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3) is the main pathway via which it exerts its action in the m...
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Objective: This study aimed to investigate the physiological role of alternative calcium conduct once contractions triggered by oxytocin and PGF? in human myometrium. This conductance, supported by TRPC and TRPV channels, may provide alternative pathways to control either free intracellular and/or submembrane Ca2+ - concentrations, which in turn wi...
This article analyzes the physiological role of pain during parturition in domestic animals, discusses the controversies surrounding the use of opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and local analgesics as treatments during labor, and presents the advantages and disadvantages for mother and offspring. Labor is a potentially stres...
Deregulation in uterine contractility can cause common pathological disorders of the female reproductive system, including preterm labor, infertility, inappropriate implantation, and irregular menstrual cycle. A better understanding of human myometrium contractility is essential to designing and testing interventions for these important clinical pr...
Preterm labor caused by uterine contractions is a major contributor to neonatal morbidity and mortality. Treatment intended to reduce uterine contractions include tocolytic agents, such as indomethacin. Unfortunately, clinically used tocolytics are frequently inefficient and cross the placenta causing fetal side effects. Here we show for the first...
One of the most established roles of oxytocin (OT) is in inducing uterine contractions and labour. Apart from contractions, our recent study have shown that OT can also activate pro-inflammatory pathways in both human myometrial and amnion cells which suggests the pro-inflammatory role of OT should be taken into account when developing tocolytics t...
Citations
... Hal tersebut karena ibu multipara sudah berpengalaman sehingga pengetahuan, persiapan serta perilaku menyusui lebih baik dibandingkan dengan ibu primipara antaralain pengalaman dalam perawatan payudara (Breast care), pengalaman pumping, pengalaman teknik menyusui yang benar, pengalaman dalam penyimpanan ASI, pengalaman dalam meningkatkan produksi ASI melalui terapi non farmakologi dan asupan nutrisi [10]. Akan tetapi ibu multipara juga bisa lebih berisiko tidak memberikan ASI eksklusif apabila jarak kehamilan terlalu dekat sehingga ibu wajib memberhentikan proses menyusui meskipun anak belum genap berusia 6 bulan, proses menyusui pada ibu hamil akan menyebabkan dampak buruk terhadap kehamilannya yaitu terjadi abortus dan kelahiran premature karena rangsangan hormone oksitosin yang dapat menyebabkan kontraksi mulut rahim [11]. ...
Abstrak ASI merupakan makanan utama dan memiliki komposisi terlengkap sesuai kebutuhan bayi yang dapat menunjang pertumbuhan dan perkembangan, akan tetapi apabila praktik pemberiannya kurang optimal maka akan berdampak serius pada masalah kesehatan seperti kurang gizi, anemia, stunting, dan risiko penyakit lainnya. Permasalahan di lapangan masih banyak ibu yang belum mengetahui tanda-tanda kecukupan ASI temasuk cara meningkatkannya, padahal indikator kelancaran ASI dapat dinilai dari volume ASI yang keluar. Tujuan penelitian ini untuk menganalisis hubungan durasi dan frekuensi menyusui dengan volume ASI yang diproduksi ibu setiap hari. Pengambilan data dilakukan pada tanggal 08-09 September 2020 di Wilayah Kerja Puskesmas Umbulharjo I. Jenis penelitian adalah survey analitik dengan pendeketan cross sectional, jumlah sample 61 ibu menyusui yang memiliki bayi usia 0-3 bulan diambil dengan teknik consecutive sampling. Analisis data univariate menggunakan distrubusi frekuensi dan bivariate menggunakan uji Gamma dan Sommers. Hasil Penelitian menunjukkan semua ibu menyusui memiliki jenis ASI matur 100%, rata-rata volume ASI 1242.869 ml, Durasi menyusui 96.7% dalam kategori normal, frekuensi menyusui 67.2% dalam kategori normal. Hasil analisis bivariate frekuensi menyusui dengan volume ASI diperoleh nilai sig 0.000 < 0.05, dan durasi menyusui dengan volume ASI diperoleh nilai sig 0.149 > 0.05. Kesimpulannya sebagian besar ibu menyusui menghabiskan waktu >10 menit s.d 30 menit setiap kali menyusui, frekuensi 8-12 kali/24 jam, rata-rata volume ASI adalah 1242 ml/24 jam. Ada hubungan frekuensi menyusui dengan volume ASI, tetapi tidak ada hubungan antara durasi menyusui dengan volume ASI. Kata kunci : Frekuensi menyusui, Durasi menyusu, Volume ASI Abstract Breast milk is the main food and has the most complete composition according to the needs of the baby which can support growth and development, however if the practice of giving is less than optimal, it will have a serious impact on health problems such as malnutrition, anemia,
... [68] Alongside atosiban, the group of OTR antagonists encompasses barusiban, characterized by its high selectivity for the oxytocin receptor (OTR), potent activity, and subcutaneous administration as well as the orally administered retosiban and nolasiban. [69][70][71][72][73]. ...
... Skeletal structure of oxytocin, arginine vasopressin, and atosiban.[73]. ...
Preterm birth presents a significant challenge in clinical obstetrics, requiring effective strategies to reduce associated mortality and morbidity risks. Tocolytic drugs, aimed at inhibiting uterine contractions, are a key aspect of addressing this challenge. Despite extensive research over many years, determining the most effective tocolytic agents remains a complex task, prompting better understanding of the underlying mechanisms of spontaneous preterm birth and recording meaningful outcome measures. This paper provides a comprehensive review of various obsolete and current tocolytic drug regimens that were instituted over the past century, examining both historical contexts and contemporary challenges in their development and adoption. The examination of historical debates and advancements highlights the complexity of introducing new therapies. While the search for effective tocolytics continues, questions arise regarding their actual benefits in obstetric care and the necessity for ongoing exploration. The presence of methodological limitations in current research emphasizes the importance of well-designed randomized controlled trials with robust endpoints and extended follow-up periods.In response to these complexities, the consideration of shifting towards prevention strategies aimed at addressing the root causes of preterm labor becomes more and more evident. This potential shift may offer a more effective approach than relying solely on tocolytics to delay labor initiation.Ultimately, effectively managing threatened preterm birth necessitates ongoing investigation, innovation, and a willingness to reassess strategies in pursuit of optimal outcomes for mothers, neonates, and long-term child health.
... This complex plays an important role in activating myosin light-chain kinase, a key enzyme responsible for inducing contractions in the myometrial muscle. 10 In decidua, oxytocin interacts with its receptor and releases prostaglandins. ...
... 12 The oxytocin system, which acts via uterine oxytocin receptors, plays a central role in the mechanisms of human parturition. Increased concentrations of oxytocin receptors appear to be important in the onset of preterm labor. 1 3 Atosiban is an oxytocin analog with modification of amino acids located at positions 1, 2, 4, and 8. 10 It competes with oxytocin binding at oxytocin receptors resulting in reduced myometrial contraction. 14 Atosiban is the only oxytocin antagonist in use for the treatment of preterm labor in Europe and other countries. ...
Objective: This prospective multicentric study
was designed to confirm the efficacy and safety
of atosiban in preterm labor.
Methods:In a study across 14 sites in India, 406
patients with preterm labor symptoms received
up to 48 hours of atosiban infusion. Tocolysis
efficacy was gauged by the 72-hour undelivered
rate, while safety was assessed via
maternal-fetal and neonatal adverse events.
Results:In 400 evaluated patients, the gestation
period in 89% of patients was prolonged for
more than 48 hours and 83.75% of patients
continued their pregnancy up to 72 hours.
Amongst the tocolyzed patients, 77% of preterm
births were prevented for more than 7 days. The
mean duration of gestational period
prolongation after the tocolysis was 31.28 days
with a mean gestational age at delivery of 35.0 ±
3.15 weeks. Singleton and twin pregnancy
prolongation rates for 72 hours were 84.95% and
67.86% respectively. Birth weight of more than
2500 grams was in 54.44% of neonates and an
APGAR score of more than 7 after 5 minutes was
in 91.82% of neonates. Patients receiving
atosiban were more likely to have nausea
(2.71%), tachycardia (2.46%), and headache
(1.97%). No new or unexpected adverse events
were reported in this study.
Conclusion: Atosiban is effective in prolonging
the gestational period by a mean of 31 days in
patients with pre-term labor, with a low
incidence of maternal-fetal adverse effects. The
requirement of ‘Neonatal Intensive Care Unit’
admission for the newborn is reduced, thus
saving a huge cost associated with
hospitalization.
... A behavioral pharmacology experiment of this design can indicate whether a specific hormone is required for the typical expression of the measured behavior. To this end, several drugs have been developed to specifically target and block OXTR, but most have been developed for peripheral action (e.g., to prevent preterm labor by antagonizing uterine OXTR 42 ) or for in vitro experimentation. In recent years, one agent has emerged as the best option to antagonize neural OXTR after peripheral delivery: L-368,899. ...
... The Merck compound L-368,899 is a commercially available, nonpeptide, small-molecule, selective OXTR antagonist that was originally developed as a drug to prevent preterm labor in humans. 27,45 Although its utility was limited for that goal because of suboptimal oral bioavailability and pharmacokinetics in primates, 13,42 the compound has been used for many decades for neuroscience research in animals to block OXTR in the brain after peripheral administration, which allows assessment of the involvement of the OXT system in social behavior. L-368,899 has been reported to accumulate in the rhesus monkey brain after peripheral administration 2 and to affect social behavior in rhesus monkeys, 2 marmoset monkeys, [5][6][7][8]20,24,35,39 lambs, 25 and a growing number of studies in rodents. ...
L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( Canis latrans ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.
... Oxytocin receptor antagonists, which mimic oxytocin with stronger receptor a nity, function by reducing prostaglandin production and calcium in ux into cells, thereby inhibiting uterine contractions [7,8]. While oxytocin receptor antagonists are commonly used for tocolysis [9,10], their application in treating ET is currently under investigation. Previous studies have indicated that administering oxytocin receptor antagonists during ET improves pregnancy outcomes. ...
Background
The primary objective of this investigation was to assess the potential improvement in pregnancy outcomes among infertile women undergoing in vitro fertilization (IVF) cycles, specifically during frozen embryo transfer (FET), following the administration of an oxytocin receptor antagonist. This study aimed to examine this impact across various subgroups, including individuals experiencing recurrent implantation failure (RIF), adenomyosis, and myoma.
Methods
This retrospective cohort study involved 431 patients who underwent their initial IVF-FET cycle at our reproductive center between January and December 2021. The study group (n = 162) received an oxytocin receptor antagonist during FET, while the control group (n = 227) underwent FET without this antagonist. A comparative analysis of baseline and cycle characteristics was conducted between the two groups, with additional subgroup analyses.
Results
There were no significant differences in baseline or cycle characteristics between the study and control groups. Overall, there was no significant difference in live birth rate between the two groups. However, in specific subgroups, the study group demonstrated significantly greater live birth rates than did the control group for patients with RIF (43.9% vs. 26.2%, P = 0.016), adenomyosis (37.7% vs. 22.1%, P = 0.039), or myoma (46.3% vs. 20.4%, P = 0.004). Multivariate analysis indicated a positive association between oxytocin receptor antagonist use and live birth rates in women with RIF (adjusted OR 2.17, 95% CI 1.08–4.35; P = 0.030), adenomyosis (adjusted OR 3.44, 95% CI 1.43–8.28; P = 0.006), and myoma (adjusted OR 3.11, 95% CI 1.23–7.85; P = 0.016).
Conclusions
While the administration of an oxytocin receptor antagonist during FET did not increase live birth rates in the overall population, it exhibited potential benefits in improving live birth rates in women with RIF, adenomyosis, or myoma.
... However, it is important to be aware that the use of oxytocin during labor has been linked to a decrease in the quantity and responsiveness of myometrial oxytocin receptors [24]. This reduced responsiveness of the receptors to oxytocin can result in a higher dosage requirement for effectively managing uterine atony and PPH, thereby making the management of PPH more challenging [25]. ...
Objective
The current study aims to evaluate the correlation between oxytocin augmentation and postpartum hemorrhage.
Method
PubMed, Web of Science, and Scopus has been searched for studies assessing the correlation between oxytocin augmentation and postpartum hemorrhage up to January 24, 2024. The search strategy included relevant keywords related to PPH and oxytocin augmentation. The risk of bias assessment was conducted by two reviewers using the Newcastle-Ottawa Scale (NOS). To pool the effects sized of included studies odds ratios (OR) of interest outcome with their 95% confidence interval (CI) were used.
Results
Eight studies were included in this meta-analysis. The pooled analysis of the included studies showed a statistically significant association between oxytocin augmentation and increased odds of PPH (pooled odds ratio [OR] = 1.27, 95% confidence interval [CI]: 1.05-1.53; I2 = 84.94%; p = 0.01). Publication bias was assessed using funnel plots, which appeared relatively asymmetrical, indicating significant publication bias. Galbraith plot and trim and fill plot were used for publication bias. Sensitivity analyses were performed by leave one out method.
Conclusion
This meta-analysis suggests that using oxytocin for labor augmentation is linked to a significant increase in the risk of PPH. It highlights the need for careful monitoring and consideration when using oxytocin, especially in low and middle-income countries where guidelines and supervision are crucial.
... Consequently, it has the potential to facilitate the process of embryo implantation by diminishing uterine peristalsis. 10 Moreover, the administration of atosiban has the potential to yield positive effects on the endometrial environment. It has been hypothesised that atosiban may improve endometrial blood flow and embryonic survival by preventing the uterus from producing prostaglandins. ...
Background
Uterine contractions may interfere with embryo implantation in assisted reproductive technology. To reduce these contractions and improve success rates, the oxytocin antagonist atosiban has been suggested for administration during embryo transfer. The aim of this study is to evaluate the effectiveness of atosiban in increasing live birth rates among women who have previously experienced a single implantation failure and are scheduled for single blastocyst transfer.
Methods and analysis
We conduct a single-centre randomised controlled study comparing atosiban and placebo in women undergoing a single blastocyst transfer with a previous failed blastocyst transfer. Women with endocrine or systemic illnesses, recurrent miscarriages, uterine malformations or fibroids, untreated hydrosalpinx, endometriosis (stage III or IV) or uterine fibroids, as well as women undergoing preimplantation genetic testing, are ineligible. The primary outcome is live birth resulting from the frozen-thawed embryo transfer. Secondary outcomes include biochemical/clinical pregnancy, miscarriage, ectopic pregnancy, multiple pregnancies as well as maternal and perinatal outcomes. We plan to recruit 1100 women (550 women per group). This will allow us to demonstrate or refute an increase in live birth rate from 40% to 50%. Data analysis will follow the intention-to-treat principle. We will measure patterns of uterine peristalsis which will allow subgroup analysis for women with or without uterine peristalsis.
Ethics and dissemination
This study has been approved by the Institutional Review Board of Northwest Women’s and Children’s Hospital (No. SZ2019001). Written informed consent will be obtained from each participant before randomisation. The results of the trial will be presented at scientific meetings and reported in publications.
Trial registration number
ChiCTR1900022333.
... Signals Downstream to G qβγ Subunits Alongside G α -subunit signaling, G αq -related G βγ subunits, mainly composed of G β5γ2 complex, are also mobilized in coordination with the activity of G αq subunit signaling, such as the induction of Cox-2, NO synthesis, and H 2 S release in OT neurons by increasing the expression of pERK1/2 and CAMK activity [6,[65][66][67]. Increases in pERK1/2 levels increase cytosolic phospholipase A2 activity that together with pERK1/2 promotes PG production [68]. The pERK1/2 signaling may also mediate lysosomal degradation of K Ca channels [69], thereby facilitating OT neuronal activity. ...
... In addition, many other signals are also involved in OTR-G q signaling, such as RhoA/Rho kinase, Akt, and AMP-activated protein kinase [37]. OT activation of G αq/11 subunit also activates RhoA/Rho kinase that increases the level of myosin light chain phosphorylation, independent of PLC-β signaling [79,80], but similar to the effect of activation of myosin light-chain kinase by Ca 2+ -calmodulin complex [68]. Figure 1 shows a diagram of sequential activation of OTR-G q protein and G s protein signaling pathways in the autoregulation of OT neuronal activity. ...
Oxytocin (OT), a hypothalamic nonaneuropeptide, can extensively modulate mental and physical activities; however, the regulation of its secretion from hypothalamic OT neurons remains poorly understood. OT neuronal activity is generally modulated by neurochemical environment, synaptic inputs, astrocytic plasticity, and interneuronal interactions. By changing intracellular signals and ion channel activity, these extracellular factors dynamically regulate OT neuronal activity and OT release in a microdomain-specific manner. In this process, OT receptor (OTR) and OTR-coupled G proteins are pivotal, typically observed during lactation. Suckling-elicited somatodendritic release of OT causes sequential activation of Gq and Gs proteins to increase the firing rate gradually and trigger burst firing transiently, and then of Gi/o protein to cause post-burst inhibition, as a result of potential bolus somatodendritic release of OT during burst. Under chronic social stress like mother-baby separation and cesarean section, excessive somatodendritic secretion of OT and over-excitation of OT neurons cause post-excitation inhibition of OT neuronal activity and reduction of OT secretion. In this process, dominance of G protein that couples to OTR is switched from Gq to OTR-Gi/o type, because of inhibition of OTR-Gq signaling following negative feedback of downstream Gq signaling or crosstalk of Gq with Gs and Gi signals. This review summarizes our current understandings of OT/OTR signaling in the autoregulation of OT neuronal activity under physiological and pathological conditions.
... In is increased [30]. In physiologic labor, endogenous oxytocin is produced pulsatile rather than continu-ously as is the case with exogenous infusion, and this mechanism likely reduces receptor desensitization. ...
Continuous electronic fetal monitoring (EFM) was first introduced commercially over 50 years ago with the hope of improving perinatal outcomes during labor. However, despite the increased use of EFM, definitive improvements in perinatal outcomes have not been demonstrated. Variance in tracing interpretation and intervention has led to increased rates of cesarean and operative vaginal deliveries and perhaps increased maternal and neonatal morbidity. Since its inception, several strategies have been developed in hopes of optimizing EFM and improving these outcomes. Tachysystole is defined as more than five contractions in 10 minutes, averaged over 30 minutes. The presence or absence of associated FHR abnormalities is the key issue in management. For women with spontaneous labor, tachysystole coupled with recurrent FHR decelerations requires evaluation and treatment. Tachysystole occurring with less frequent FHR abnormalities may or may not require treatment, depending on the specific clinical situation and associated FHR characteristics such as variability and accelerations. In laboring women receiving oxytocin, management of tachysystole generally involves efforts to reduce uterine activity to minimize risk of evolving fetal hypoxemia or acidemia. In labor induction or augmentation or both, a decrease in the oxytocin dose should be considered if tachysystole occurs in the presence of a Category I tracing. If there is a Category II or III tracing, oxytocin should be reduced or stopped in addition to intrauterine resuscitation. In addition, simultaneous initiation of multiple resuscitative measures may improve fetal condition more rapidly than the use of individual therapies (Table 2). If tachysystole induced FHR abnormalities do not resolve with these initial maneuvers, then tocolytic medications (eg, terbutaline) may be warranted.
... It has been hypothesized that this improvement could derive from a reduction in the ability of the endometrium to produce prostaglandins, the classical cause of primary dysmenorrhea [19][20][21]. According to another hypothesis, the drastic reduction in adrenergic fibers and uterine noradrenaline that occurs in preparation for labor could become a permanent feature, therefore attenuating dysmenorrhea after birth [18,22]. ...
During pregnancy, the uterus undergoes several modifications under the influence of hormonal and mechanical stimuli. We hypothesize that while most of these modifications are reverted during involution, some of the physiological properties of the uterus are permanently altered. To investigate this hypothesis, we conducted motility experiments to evaluate the contractility response of uterine tissue samples from non-pregnant virgin and proven breeder female rats to oxytocin (10 ⁻¹⁰ to 10 ⁻⁵ M). We found that the virgin tissue contracts more robustly than proven breeder tissue in the absence of oxytocin, yet with oxytocin, proven breeder samples displayed a significantly higher increase in activity. These results could depend on a more elevated expression of oxytocin receptor and/or on an alteration in the intracellular pathways affected by the activation of the oxytocin receptors. Here, we explored the impact of some structures involved in the management of intracellular calcium on the dose response to oxytocin recorded from virgin and proven breeder uterine strips. Specifically, we replicated the dose response experiments in low extracellular calcium (10 μM), in the presence of the intracellular calcium channel blocker ruthenium red (10 μM), and in the presence of the sarcoplasmic-endoplasmic reticulum calcium ATP-ase pump inhibitor, cyclopiazonic acid (10 μM). The results of these experiments suggest that also the expression of proteins that control intracellular calcium availability is affected by the experience of pregnancy. Molecular biology experiments will give us more detail on the magnitude of these expression changes.
